Linzess

SIDE EFFECTS

Clinical Trials Experience

Because clinical trials are conducted under widely
varying conditions, adverse reaction rates observed in the clinical trials of a
drug cannot be directly compared with rates in the clinical trials of another
drug and may not reflect the rates observed in practice.

During clinical development, approximately 2570, 2040,
and 1220 patients with either IBS-C or CIC were treated with LINZESS for 6
months or longer, 1 year or longer, and 18 months or longer, respectively (not
mutually exclusive).

Irritable Bowel Syndrome with Constipation (IBS-C)

Most Common Adverse Reactions

The data described below reflect exposure to LINZESS in
the two placebo-controlled clinical trials involving 1605 adult patients with
IBS-C (Trials 1 and 2). Patients were randomized to receive placebo or 290 mcg
LINZESS once daily on an empty stomach for up to 26 weeks. Demographic
characteristics were comparable between treatment groups [seeClinical
Studies]. Table 1 provides the incidence of adverse reactions reported in
at least 2% of IBS-C patients in the LINZESS treatment group and at an
incidence that was greater than in the placebo group.

Table 1: Adverse Reactions Reported in at least 2% of
LINZESS-treated Patients and at an Incidence Greater than in Placebo Group
Patients in the Two Phase 3 Placebo-controlled Trials (1 and 2) in IBS-C

Diarrhea

Diarrhea was the most commonly
reported adverse reaction of the LINZESS-treated patients in the pooled IBS-C
pivotal placebo-controlled trials. In these trials, 20% of LINZESS-treated
patients reported diarrhea compared to 3% of placebo-treated patients. Severe
diarrhea was reported in 2% of the LINZESS-treated patients versus less than 1%
of the placebo-treated patients, and 5% of LINZESS-treated patients
discontinued due to diarrhea vs less than 1% of placebo-treated patients. The
majority of reported cases of diarrhea started within the first 2 weeks of LINZESS
treatment. Fecal incontinence and dehydration were each reported in less than
or equal to 1% of patients in the LINZESS treatment group [see WARNINGS AND
PRECAUTIONS].

Adverse Reactions Leading to
Discontinuation

In placebo-controlled trials in
patients with IBS-C, 9% of patients treated with LINZESS and 3% of patients
treated with placebo discontinued prematurely due to adverse reactions. In the
LINZESS treatment group, the most common reasons for discontinuation due to
adverse reactions were diarrhea (5%) and abdominal pain (1%). In comparison,
less than 1% of patients in the placebo group withdrew due to diarrhea or
abdominal pain.

Adverse Reactions Leading to
Dose Reductions

In the open-label, long-term
trials, 2147 patients with IBS-C received 290 mcg of LINZESS daily for up to 18
months. In these trials, 29% of patients had their dose reduced or suspended
secondary to adverse reactions, the majority of which were diarrhea or other GI
adverse reactions.

Other Adverse Reactions

Adverse reactions that were
reported in at least 1% and less than 2% of IBS-C patients in the LINZESS
treatment group and at an incidence greater than in the placebo treatment group
are listed below by body system:

Other Adverse Events

In placebo-controlled trials in
patients with IBS-C, less than 1% LINZESS-treated patients and no
placebo-treated patients reported hematochezia; no patient in either treatment
group reported melena. Less than 1% of LINZESS-treated and placebo-treated
patients reported allergic reactions, urticaria, or hives as adverse events.

Chronic Idiopathic Constipation (CIC)

Most Common Adverse Reactions

The data described below reflect exposure to LINZESS in
the two double-blind placebo-controlled clinical trials of 1275 adult patients
with CIC (Trials 3 and 4). Patients were randomized to receive placebo or 145
mcg LINZESS or 290 mcg LINZESS once daily on an empty stomach, for at least 12
weeks. Demographic characteristics were comparable between both LINZESS
treatment groups and placebo [seeClinical Studies]. Only data for the
recommended LINZESS 145 mcg dose and placebo are presented. Table 2 provides
the incidence of adverse reactions reported in at least 2% of CIC patients in
the 145 mcg LINZESS treatment group and at an incidence that was greater than in
the placebo treatment group.

Table 2: Adverse Reactions Reported in at least 2% of
145 mcg LINZESS-treated Patients and at an Incidence Greater than in Placebo
Group Patients in the Two Phase 3 Placebo-controlled Trials (3 and 4) in CIC

Diarrhea

Diarrhea was the most commonly
reported adverse reaction of the LINZESS-treated patients in the pooled CIC
placebo-controlled trials. In these trials, 16% of LINZESS-treated patients
reported diarrhea compared to 5% of placebo-treated patients. Severe diarrhea
was reported in 2% of the 145 mcg LINZESS-treated patients versus less than 1%
of the placebo-treated patients, and 5% of LINZESS-treated patients
discontinued due to diarrhea vs less than 1% of placebo-treated patients. The
majority of reported cases of diarrhea started within the first 2 weeks of
LINZESS treatment. Fecal incontinence was reported in 1% of patients in the
LINZESS treatment group, compared with less than 1% in the placebo group.
Dehydration was reported in less than 1% of patients in the LINZESS treatment
group [see WARNINGS AND PRECAUTIONS].

Adverse Reactions Leading to
Discontinuation

In placebo-controlled trials in
patients with CIC, 8% of patients treated with LINZESS and 4% of patients
treated with placebo discontinued prematurely due to adverse reactions. In the
145 mcg LINZESS treatment group, the most common reasons for discontinuation
due to adverse reactions were diarrhea (5%) and abdominal pain (1%). In
comparison, less than 1% of patients in the placebo group withdrew due to
diarrhea or abdominal pain.

Adverse Reactions Leading to
Dose Reductions

In the open-label, long-term
trials, 1129 patients with CIC received 290 mcg of LINZESS daily for up to 18
months. In these trials, 27% of patients had their dose reduced or suspended
secondary to adverse reactions, the majority of which were diarrhea or other GI
adverse reactions.

Other Adverse Reactions

Adverse reactions that were reported in at least 1% of
and less than 2% of CIC patients in the 145 mcg LINZESS treatment group and at
an incidence greater than in the placebo treatment group are listed below by
body system:

Other Adverse Events

In placebo-controlled trials in patients with CIC, less
than 1% of both LINZESS-treated and placebo-treated patients reported rectal
hemorrhage, hematochezia or melena. Less than 1% of LINZESS-treated and
placebo-treated patients reported allergic reactions, urticaria, or hives as
adverse events.

DRUG INTERACTIONS

No drug-drug interaction studies have been conducted with
LINZESS. Linaclotide and its active metabolite are not measurable in plasma
following administration of the recommended clinical doses; hence, no systemic drug-drug
interactions or drug interactions mediated by plasma protein binding of
linaclotide or its metabolite are anticipated [see CLINICAL PHARMACOLOGY].

Linaclotide does not interact with the cytochrome P450
enzyme system based on the results of in vitro studies. In addition,
linaclotide is neither a substrate nor an inhibitor of the efflux transporter
Pglycoprotein (P-gp).

Last reviewed on RxList: 7/25/2014
This monograph has been modified to include the generic and brand name in many instances.